tbuckley/cabot-search huggingface dataset:
Abstract P1121: Transposition Of Great Arteries - Genetics And Beyond
Authors: Sohrab Singh, Joseph Heaton, Dhairya Nanavaty, Sarath Reddy
Journal: Circulation Research (2022)

Background: Transposition of great arteries (TGA) is one of the most common severe congenital heart defects and neonatal cyanotic heart diseases. Given contribution of several molecular pathways involved in cardiac differentiation (Fig.1), the etiology governing morphogenesis of TGA remains largely unknown. There is greater insight into interactions and molecular variations culminating in aortic-pulmonary transposition. Clinical evidence and genetic sequencing has led to several polymorphic mutations demonstrating phylogenetic conservation of regulatory domains. Defects in transcription factors involved in nodal signaling, in addition to ZIC3 &amp; PROSIT 240, are strongly implicated in arterial transposition. We reviewed current literature on the genetics determining TGA development and associated lateral syndromes Methods: We searched PubMed, Scopus, Web of Science, and Google Scholar to identify listed keywords Body: TGA is now postulated as part of a spectrum of genetic disorders with familial recurrence, rather than sporadic defect. Evidence exists for TGA's correlation with genes involving lateralization defects, heterotaxy and asplenia. Evidence, albeit scarce, has surfaced depicting association of TGA with genetic syndromes like Trisomy 8, 18, VACTERL and CHARGE syndrome, Tuberous sclerosis, Deletion 11q, 18p, and other genetic syndromes like Digeorge, Turner’s, Noonan’s, Williams, and Marfan. Additional gene mutations causing TGA might include CFC-1, TRAP2, FOXH1, LEFTY2, PITX2, GDF1. The interrelation between mutations in ciliary genes contributing to both TGA and neurodevelopment disorder, prompts consideration of common ciliopathic pathogenies explaining association between TGA and neurodevelopmental disorders. Conclusion: The occurrence of mutations in a single gene, though a cause for TGA, does not correlate with 5-7% occurrence rate for TGA. Major research has focused on a single gene approach, neglecting the simultaneous screening for other susceptible targets. The multiple-hit model suggested by De Luca et al. (2010) is a promising approach for further understanding the contribution of multi-gene sequences. Minor genetic variations in several genes may have a cumulative effect that increases disease susceptibility in TGA and other congenital heart defects
Abstract P3102: Matrine Inhibits Advanced Glycation End Products- Inducedmatrine Inhibits Advanced Glycation End Products- Induced Macrophage M1 Polarization By Reducing Dnmt3a/b- Mediated Dna Methylation Of Gpx1 Promoter
Authors: Zhongwei Liu, Yujie Xing
Journal: Circulation Research (2022)

Background and Objective: Advanced glycation end products (AGEs) are characterized diabetic metabolites inducing macrophage M1 polarization which is crucial in diabetes- exacerbated atherosclerosis. Matrine was proved anti-atherosclerotic. The current study was aimed to investigate the inhibitory effects of matrine on AGEs- induced macrophage M1 polarization and underlying molecular mechanisms. Methods: Primary mouse macrophages were exposed to AGEs. Receptor for AGEs (RAGE) and toll-like receptor 4 (TLR4) were over-expressed by vectors. Matrine was used to treat these cells. Inducible nitric oxide synthase (iNOS) expression and pro-inflammatory cytokine production were used to evaluate macrophage M1 polarization. Oxidative stress was assessed by intracellular reactive oxygen species (ROS) generation, total antioxidant capacity (TAC) and malondialdehyde (MDA) contents. Relative mRNA expression level was determined by real-time PCR. Western blotting was used to evaluate protein and protein phosphorylation levels. Bisulfite sequencing PCR (BSP) was used to evaluate DNA methylation. Results: Matrine inhibited AGEs- induced macrophage M1 polarization which was impaired by RAGE and TLR4 over-expressions. Matrine reduced AGEs exposure elevated expressions of DNMT3a and DNMT3b in macrophages, which further decreased DNA methylation of GPX1 promoter. Increased GPX1 by matrine suppressed oxidative stress in AGEs- exposed macrophages which was impaired by RAGE over-expression. Conclusions: Matrine inhibited AGEs- induced macrophage M1 polarization by suppressing RAGE-induced oxidative stress-mediated TLR4/STAT1 signaling pathway. Matrine exerted anti-oxidant effects via increasing GPX1 expression by inhibiting DNMT3a/b- induced GPX1 promoter DNA methylation.
Tea-dust induced asthma
Authors: JA Roberts, NC Thomson
Journal: European Respiratory Journal (1988)

A 55-yr old female worker in a tea-packing production line developed asthma to tea-dust. She had no previous history of chest disease, and skin prick testing to a solution of tea-dust and to a variety of common allergens were all negative. Diagnosis was established by serial peak expiratory flow rate readings. Bronchial provocation challenge with tea-dust demonstrated a late asthmatic reaction.
New drugs for asthma
Authors: PJ Barnes
Journal: European Respiratory Journal (1992)

Several new drugs are now under development for the treatment of asthma, either as improvements to existing classes of therapy or as novel agents. Amongst bronchodilators, long-acting inhaled beta 2-agonists (salmeterol and formoterol) look very promising and there is also interest in selective phosphodiesterase inhibitors, K+ channel-openers and nitrodilators. There are several new inhaled corticosteroids under development and more selective agents include leukotriene antagonists, 5-lipoxygenase inhibitors, bradykinin and tachykinin antagonists and immunomodulators. In the future, adhesion molecule inhibitors and cytokine inhibitors may be developed.
Abstract P2035: Palmitoylation Of Rac1 Is Required For Cardiomyocyte Hypertrophy And Oxidative Stress
Authors: James P Teuber, Arasakumar Subramani, Yasin Farhan, Matthew Brody
Journal: Circulation Research (2022)

Cardiac hypertrophy, the enlargement of cardiomyocytes in response to an increased workload, is a precursor to maladaptive cardiac remodeling and heart failure. Palmitoylation is a post-translational lipid modification which controls the subcellular localization, trafficking, and activity of proteins but has not been extensively studied in the setting of cardiac disease. Previous work from our group shows that transgenic mice with cardiomyocyte-specific overexpression of zDHHC3, a S-acyltransferase which catalyzes palmitoylation, develop severe cardiac hypertrophy which progresses to lethal dilated cardiomyopathy. Palmitoylated levels, as well as total expression, of the small GTPase Rac1 were significantly elevated in the hearts of these transgenic mice compared to control mice suggesting that palmitoylation of Rac1 at Cys-178 may drive this phenotype. Rac1 is required for the development of cardiac hypertrophy and relatedly plays an important role in mediating myocardial oxidative stress as a regulatory subunit of the NADPH oxidase 2 (Nox2) complex. Interestingly, transgenic mice overexpressing zDHHC3 in cardiomyocytes also display increased myocardial oxidative stress. Because of the known importance of Rac1 in regulating cardiac remodeling, we sought to define the role of palmitoylation in controlling Rac1 signaling in cardiomyocytes. To do this, we overexpressed a constitutively active Rac1 mutant, Rac1-G12V, or a constitutively active, palmitoylation-deficient Rac1 mutant, Rac1-G12V/C178S, in neonatal rat cardiac myocytes (NRCMs). Our data suggest that inhibition of Rac1 palmitoylation at Cys-178 protects NRCMs from hypertrophy and oxidative stress induced by hyperactive Rac1 signaling. Furthermore, we found that overexpression of palmitoylation-deficient Rac1 protects against oxidative stress induced by angiotensin II in NRCMs. Future work will interrogate if inhibition of Rac1 palmitoylation at Cys-178 in cardiomyocytes protects against the development of cardiac hypertrophy and myocardial oxidative stress in vivo .
Stable Ischemic Heart Disease (Japanese Version)
Authors: Daniel Katz, Michael C. Gavin
Journal: Annals of Internal Medicine (2019)

In the Clinic6 August 2019Stable Ischemic Heart Disease (Japanese Version)FREEDaniel Katz, MD and Michael C. Gavin, MD, MPHDaniel Katz, MDBeth Israel Deaconess Medical Center, Boston, Massachusetts (D.K., M.C.G.) and Michael C. Gavin, MD, MPHBeth Israel Deaconess Medical Center, Boston, Massachusetts (D.K., M.C.G.)Author, Article, and Disclosure Informationhttps://doi.org/10.7326/IsTranslatedFrom_AITC201908060_Japanese SectionsAboutVisual AbstractPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Editors' Note: This article (available in PDF format) is the translated Japanese version of In the Clinic: Stable Ischemic Heart Disease (Katz D, Gavin MC. Stable Ischemic Heart Disease. Ann Intern Med. 2019;171:ITC17-ITC32. doi:10.7326/AITC201908060. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: Beth Israel Deaconess Medical Center, Boston, Massachusetts (D.K., M.C.G.)Acknowledgment: The authors thank Jennifer Fisher Wilson, author of the previous version of this In the Clinic.Funding Source: American College of Physicians.Disclosures: Authors have disclosed no conflicts of interest. Forms can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0119.With the assistance of additional physician writers, the editors of Annals of Internal Medicine develop In the Clinic using MKSAP and other resources of the American College of Physicians.In the Clinic does not necessarily represent official ACP clinical policy. For ACP clinical guidelines, please go to https://www.acponline.org/clinical_information/guidelines/. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetailsSee AlsoStable Ischemic Heart Disease Daniel Katz and Michael C. Gavin Metrics 6 August 2019Volume 171, Issue 3Page: JITC17-JITC32 ePublished: 15 November 2022 Issue Published: 6 August 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.PDF downloadLoading ...
Abstract P1002: Elucidating The Role Of Dyrk1a Kinase In Controlling Cardiomyocyte Proliferation
Authors: Giorgia Rizzari, Ellen Dirkx, Consuelo Torrini, Mateusz Tomczyk, Miguel Mano, Mauro Giacca
Journal: Circulation Research (2022)

Despite the development of new pharmacological and device-based therapies, no approaches currently exist to compensate for the irreversible loss of cardiomyocytes occurring after myocardial infarction. In a search for novel treatments that induce cardiomyocyte proliferation, we performed a high-content, fluorescence-microscopy-based, high-throughput screening in neonatal rat cardiomyocytes, using a library of FDA/EMA-approved drug library compounds. The screening, which was based on EdU incorporation as an S-phase marker, identified harmine as the most powerful drug enhancing proliferation in combination with miR-199a-3p and miR-590-3p, the most effective microRNAs that the laboratory had previously identified. Harmine treatment of CD1 mice showed an improved cardiac outcome upon harmine treatment compared to controls. Harmine is a potent inhibitor of the Dyrk1 family of protein kinases, with high specificity for the Dyrk1a isoform. Dyrk1a downregulation experiments in neonatal rat ventricular cardiomyocytes showed increased proliferation, consistent with a negative role of this kinase. The simultaneous knockdown of YAP1 blunted the effect of Dyrk1a downregulation. Of note, the YAP total protein levels were unchanged upon either Dyrk1a silencing or overexpression, but there was a marked modification of YAP subcellular localisation, being YAP1 nuclear upon knockdown and mostly cytoplasmic upon overexpression. Dyrk1a downregulation and harmine treatment activated YAP-controlled gene expression. In the course of these experiments, we also noticed a reciprocal regulation of YAP onto DYRK1a, as YAP downregulation markedly decreased Dyrk1a protein levels. This finding was reinforced by the observations that, in cardiomyocytes, the YAP-TEAD inhibitor verteporfin also decreased Dyrk1a protein levels. Of note, this downregulation was not rescued by the proteasome inhibitor MG132, thus indicating that the level of regulation is most likely transcriptional. These results support the role of Dyrk1a as an anti-proliferative factor in cardiomyocytes and highlight a novel feedback connection between Dyrk1a and YAP.
Human Immunodeficiency Virus Infection in Urban Rwanda
Authors: Susan Allen
Journal: JAMA (1991)

<h3>Objective.</h3> —To determine behavioral and demographic risk factors for human immunodeficiency virus (HIV) infection in central Africa. <h3>Design.</h3> —Cross-sectional survey. <h3>Setting.</h3> —Kigali, Rwanda. <h3>Participants.</h3> —A representative sample of 1458 childbearing women aged 19 to 37 years who were recruited from outpatient prenatal and pediatric clinics at the only community hospital in the city. <h3>Main Outcome Measure.</h3> —Antibodies to HIV assessed by enzyme immunoassay and confirmed by Western blot or indirect immunofluorescence. <h3>Results.</h3> —The HIV seroprevalence was 32% overall. Infection rates were higher in women who were single, in those in steady relationships that began after 1981, and in the 33% of women reporting more than one lifetime sexual partner. Women in legal marriages or monogamous partnerships had lower rates of infection, but even low-risk women had prevalences on the order of 20%. History of venereal disease in the past 5 years, although the strongest risk factor in a multiple logistic analysis (odds ratio, 2.7; 95% confidence interval, 2.0 to 3.7), was reported by only 30% of those infected. Having a male sexual partner who drank alcohol or who had higher income were significant risk factors for HIV infection in the multivariate analysis, but use of oral contraceptives and having an uncircumcised partner were not. <h3>Conclusions.</h3> —The epidemic of the acquired immunodeficiency syndrome in Rwanda has spread beyond high-risk groups to the general population of women without known risk factors. For most of these women, a steady male partner is the source of their HIV risk and therefore a vital target for intervention efforts. (JAMA. 1991;266:1657-1663)
Global Epidemiology of Tuberculosis
Authors: Mario C. Raviglione
Journal: JAMA (1995)

This article describes the global epidemiology of tuberculosis and reviews recent estimates of tuberculosis incidence and mortality in the world. The highest prevalence of tuberculosis infection and estimated annual risk of tuberculosis infection are in sub-Saharan Africa and Southeast Asia. Overall, almost 3.8 million cases of tuberculosis were reported in the world in 1990, of which 49% were in Southeast Asia. From the period 1984 through 1986 to the period 1989 through 1991, notification rates increased in all World Health Organization regions, except the American and the European regions. In 1990, there were an estimated 7.5 million cases of tuberculosis and 2.5 million deaths worldwide. The human immunodeficiency virus epidemic is causing increases in the number of tuberculosis cases, particularly in Africa, although increases are also expected in Southeast Asia. In many industrialized countries, tuberculosis has recently failed to decline, and in eastern Europe and the former Soviet Union, cases and deaths are increasing. Drug resistance is a serious problem, especially in the United States. If worldwide control of tuberculosis does not improve, 90 million new cases and 30 million deaths are expected in the decade 1990 through 1999. (<i>JAMA</i>. 1995;273:220-226)
Early results of the monoclonal antibody OVTL3 in specific detection of ovarian cancer.
Authors: A A Epenetos, J P Lavender, P Kenemans, L Poels
Journal: Journal of Clinical Oncology (1987)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1987.5.1.160 Journal of Clinical Oncology - published online before print September 22, 2016 PMID: 3806157 Early results of the monoclonal antibody OVTL3 in specific detection of ovarian cancer. A A EpenetosxA A EpenetosSearch for articles by this author , J P LavenderxJ P LavenderSearch for articles by this author , P KenemansxP KenemansSearch for articles by this author , L PoelsxL PoelsSearch for articles by this author https://doi.org/10.1200/JCO.1987.5.1.160 PDF "Early results of the monoclonal antibody OVTL3 in specific detection of ovarian cancer.." Journal of Clinical Oncology, 5(1), p. 160© 1987 by American Society of Clinical Oncology
Abstract P2109: Elaborating Safety Margins To Predict Drug Proarrhythmia Using Deep Learning And Patient-derived IPSCs.
Authors: Ricardo Serrano, Dries Feyen, Arne A Bruyneel, Anna Hnatiuk Hnatiuk, Michelle Vu, Prashila Amatya, Isaac Perea Gil, Maricela Prado, Timon Seeger, Joseph C Wu, Ioannis Karakikes, Mark Mercola
Journal: Circulation Research (2022)

Introduction: Drug-induced arrhythmias are a common cause for drug attrition during development and for restricted use or withdrawal from the market. Cell based assays to assess arrhythmia risk typically rely on the quantification of waveform features - e.g. action potential prolongation and after depolarizations - in the cells’ action potential. However, the predictive power of these approaches is limited. Hypothesis: We hypothesize that deep learning can extract features relevant to discriminating input classes in a systematic and unbiased manner, effectively removing the need for human-defined metrics. This can lead to a new model to estimate torsadogenic risk of drugs and evaluate the influence of myopathic gene variants on drug-induced arrhythmia. Methods: We optically recorded action potentials optically recorded for 40 drugs - characterized high, intermediate, and low or no torsadogenic risk in patients- at 8 concentrations in hiPSC-CMs from 3 healthy donors and 5 hiPSC-CMs isogenic lines carrying 5 gene variants that cause dilated and hypertrophic cardiomyopathies. We designed a convolutional neural network (CNN) to classify non-arrhythmic, arrhythmic and asystolic traces in hiPSC-CMs. Using the class probabilities measured by the CNN, we created torsadogenic and asystolic safety margins for each drug and cell line. Results: The arrhythmic class probability computed by the CNN, provided a continuous, dose-dependent metric of the proarrhythmic risk of drugs in healthy and cardiomyopathic hiPSC-CMs. We used this metric to estimate safety margins for drug-induced arrhythmia and achieved a 0.942 AUC in classifying drugs of high-intermediate risk from safe ones. We used this approach to discern the contribution of putative genetic risk factors to arrhythmia susceptibility by comparing the risk profiles of the same drugs in healthy and isogenic hiPSC-CMs carrying causal HCM and DCM gene variants that are associated with arrhythmia in patients. Conclusions: We conclude that deep learning algorithms can effectively evaluate proarrhythmic risk of small molecules. Moreover, they can also be used to discern heightened arrhythmic risk caused by genetic mutations that increase the propensity for drug-induced arrhythmia in patients.
Abstract P2060: Comprehensive Analysis Of 3’ End Sequencing Reveals Novel Polyadenylation Signals In Human Left Ventricle Failure
Authors: Rahul Neupane, Hari Krishna Yalamanchili, Keith Youker, Eric J Wagner, Arvind Bhimaraj, Harry Karmouty-Quintana, Ashrith Guha, Rajarajan Amirthalingam Thandavarayan
Journal: Circulation Research (2022)

Background: Alternative polyadenylation (APA) regulates the genes post-transcriptionally and generates mRNA isoforms with different lengths of 3’ untranslated regions (3’UTR). APA dictates diverse cellular processes such as development, differentiation, metabolism, and protein localization. The dysregulation of APA leading to global 3’UTR changes has been well studied in several human diseases including cancer. However, the role of APA in the progression of cardiac fibrosis and eventually the left ventricle (LV) heart failure in patients remains elusive. Objective: To identify whether APA regulates the 3’UTR length in the failing LV hearts compared to the healthy hearts. Methods and Results: We used Poly(A)-Click-Seq to sequence the 3’ end of the transcripts and the PolyA-miner algorithm to comprehensively quantify the APA events in healthy and failing human LV specimens. We used the Poly-A index, a metric that determines the magnitude and position of the 3’UTR changes, to determine the shortening versus lengthening of 3′UTRs. Based on these scores, we identified more than 1000 genes with a significant shift in cleavage site usage in failing LV hearts compared to healthy. Moreover, the enrichment of these differentially regulated APA candidates revealed pathways involved in the progression of heart failure and molecular functions related to mRNA binding. So, by examining the differential polyadenylation events in these hearts, we identified disease-specific APA signatures. In addition, we also found the dysregulation in the core APA machinery proteins such as cleavage factor Im (CFIm) 25, 59, and 68 in the LV failing hearts compared to the healthy. Conclusion: Hence, we demonstrated that the regulation of the 3’UTR length through APA provides an extra layer of gene expression in human LV failure. Our results provide genome-wide polyadenylation maps of the human heart and show that APA of mRNA is dynamic in the progression of LV failure.
Abstract P2121: Modeling Genetic Dilated Cardiomyopathies With Engineered Heart Tissues From Patient-derived And Isogenic Mutant Induced Pluripotent Stem Cells
Authors: Jonathan H Tsui, Bernardo Zepeda, Stephanie S Steltzer, Jaclyn J Ho, James Priest, Timothy Hoey
Journal: Circulation Research (2022)

The availability of human induced pluripotent stem cells (hiPSCs) has offered the possibility to study human-derived models of different genetic strata of cardiomyopathy for mechanistic discovery and therapeutic development. However, the phenotypes derived from cardiomyocytes differentiated from hiPSCs in conventional 2-dimensional culture systems often fail to reproducibly model clinical presentations, thereby reducing the translatability of readouts from these assays. Here we report 3-dimensional engineered heart tissues (EHTs) produced with a variety of cell lines harboring patient-derived mutations (TTN, RBM20, BAG3) known to cause dilated cardiomyopathy (DCM) which recapitulate contractile deficits associated with DCM. Internal development of EHTs also recapitulate contractile defects with small interfering RNA (siRNA) knockdown models of haploinsufficiency across multiple disease states. These observed findings with EHTs suggests improved maturity in cardiomyocytes through the presentation of microenvironmental cues akin to those seen in vivo . With continued advances in EHT technologies and capabilities, this platform may serve to significantly reduce drug candidate attrition, as well as provide new insights into pathology, prototyping of therapeutic approaches, and mechanism of action that were previously difficult to obtain.